Emtricitabine is a known antiviral drug of formula
also known under the trade name Coviracil® or FTC (Merck Index, Ed. 2001, No. 3597).
The compound, as illustrated in Figure Ia, is the cis enantiomer having the 2R,5S absolute configuration, and its chemical name is 4-amino-5-fluoro-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidin-2-one (CAS). The other optical isomers, i.e. the cis 2S,5R enantiomer (Ib) and the trans enantiomers 2S,5S (Ic) and 2R,5R (Id), have lower therapeutic activity and are therefore found to be of reduced interest in application.
Various routes for synthesizing emtricitabine are described in the literature.
For example, in international patent application WO 92/14743 (Emory University), the racemic mixture of cis isomers is prepared via standard reactions and by resolution, mainly enzymatic resolution, gives the desired 2R,5S enantiomer.
Stereoselective synthetic routes were subsequently developed, which, by means of the use of chiral auxiliaries such as menthol, allow the desired stereochemistry to be induced and allow emtricitabine to be obtained directly as a single enantiomer. U.S. Pat. No. 5,696,254 (BioChem Pharma Inc.) illustrates just this type of synthetic approach, applied to the synthesis of emtricitabine, as shown, for example, in Scheme 2B (columns 13 and 14) below:

In this scheme, the trans oxathiolane is prepared (step 1, VIII) which, when acetylated (step 2, IX) and condensed with 1-menthol, leads to the mixture of intermediate diastereoisomers (step 3, X). The desired diastereoisomer is isolated by fractional crystallization (step 4) and coupled with silylated 5-fluorocytosine (III) (step 5), leading to the derivative XI (which is referred to hereinbelow as XIa), which, finally, by reductive removal of the chiral auxiliary (step 6), gives emtricitabine (right-hand columns 15-16, erroneously represented with inversion of configuration in position 5 of the oxathiolane).
The chiral auxiliary used is 1-menthol (II), the chiral centres of which have the 1′R,2′S, 5′R absolute configuration, as illustrated below:

However, in the experimental section of the patent, discrepancies are observed relating to the stereochemistry of the intermediates used to obtain emtricitabine.
In fact, Example 21 (column 43) correctly asserts that to prepare emtricitabine, the formula of which is clearly given at the start of that example, the final reduction should be performed on the compound (1′R,2′S,5′R)-menthyl 5S-(5″-fluorocytosin-1-yl)-1,3-oxathiolane-2R-carboxylate—i.e. on intermediate XIa of scheme 2B above—as illustrated below:

The correct stereochemistry of this sequence, i.e. the use of L-menthol to induce the desired chirality corresponding to emtricitabine, was confirmed experimentally by us and subsequently reinforced as described in U.S. Pat. No. 6,051,709 (Glaxo), which will be discussed later.
In the experimental section of U.S. Pat. No. 5,696,254 (BioChem Pharma Inc.) the preparation of the desired intermediate XIa (having the 1′R,2′S,5′R chirality on the menthol and the 2R,5S chirality on the oxathiolane) does not, however, appear, since Example 18 relates to the derivative XI inverted on the oxathiolane (XIb, 1′R,2′S,5′R-2S,5R), which is thus unsuitable for producing emtricitabine, whereas Example 19 relates to the derivative XI inverted on the menthol (XIc, 1′S,2′R,5′S—R2,5S).
Also, U.S. Pat. No. 6,051,709 (Glaxo), mentioned above, describes a stereoselective process for the synthesis of cis nucleosides, this process differing from the above process essentially by the use of leaving groups (L) other than acetate—such as halo, cyano or sulphonate—in the coupling reaction of the intermediate X with the activated 5-fluorocytosine III.
However, the experimental illustration is limited to the preparation of the non-fluoro analogue of emtricitabine, known as lamivudine (Merck Index, Ed. 2001, No. 5367), as illustrated in scheme 1, columns 9-10, without any indication regarding the actual process yields. Example 1 describes the preparation of 5-hydroxyoxathiolane required by reacting 1-menthyl glyoxalate and dithianediol (part a, column 10), and the subsequent formation of the chloro derivative (part b, column 10) and its coupling reaction with cytosine silylate (last paragraph, column 10—first paragraph, column 11). The resulting product, which precipitates from the reaction medium, is recovered by simple filtration and subjected to reductive removal of the chiral auxiliary to give the crude lamivudine, which is purified, not by direct crystallization of the base but of the salified form, in particular of the salicylate. It is obvious that, by this procedure, a subsequent basic treatment will be necessary to release the lamivudine base from its salt.
This procedure, which does not appear to present any particular implementation difficulties in the case of lamivudine, becomes entirely inapplicable when used for the preparation of emtricitabine.
Specifically, we have been able to verify experimentally that the product XIa, resulting from the coupling reaction of the activated 5-fluorocytosine III with the appropriate acetate X (scheme 2B of U.S. Pat. No. 5,696,254) or with the corresponding analogue of formula
containing another leaving group (L) instead of acetate (U.S. Pat. No. 6,051,709), is not a filterable solid at all as in the case of lamivudine, but a gel that is inseparable from its mother liquors by simple filtration, and can be purified only by chromatography.
The entire stereoselective synthesis discussed hereinabove, when applied to emtricitabine, thus becomes difficult to implement industrially on account of the problems of isolation and purification of the key intermediate XIa.